Highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using same

ABSTRACT

The present invention relates to highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using therefor. The invention involves a multi-step synthesis to produce the lactam compounds. In one step of the reaction sequence, asymmetric hydrogenation of a lactam-enamide was performed to produce an intermediate that can ultimately be converted to a series of pharmaceutical compounds. The invention also contemplates the in situ synthesis of an intermediate of the multi-step synthesis, which provides economic advantages to the overall synthesis of the lactam compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States ProvisionalApplication Nos. 60/236,564, filed Sep. 29, 2000, and 60/264,411, filedJan. 26, 2001, both entitled “Phosphino-Aminophosphines,” whichapplications are hereby incorporated by this reference in theirentireties.

BACKGROUND OF THE INVENTION

[0002] Asymmetric catalysis is the most efficient method for thegeneration of products with high enantiomeric purity, as the asymmetryof the catalyst is multiplied many times over in the generation of thechiral product. These chiral products have found numerous applicationsas building blocks for single enantiomer pharmaceuticals as well as insome agrochemicals. The asymmetric catalysts employed can be enzymaticor synthetic in nature. The latter types of catalyst have much greaterpromise than the former due to much greater latitude of applicablereaction types. Synthetic asymmetric catalysts are usually composed of ametal reaction center surrounded by an organic ligand. The ligandusually is generated in high enantiomeric purity, and is the agentinducing the asymmetry. A prototypical reaction using these types ofcatalyst is the asymmetric hydrogenation of enamides to affordamino-acid derivatives (Ohkuma, T.; Kitamura, M.; Noyori, R. InCatalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: NewYork, 2000; pp. 1-17).

[0003] Although the preparation of enamides through Homer-Emmons Wittigchemistry is known, the preparation and use of substrates such aslactam-substituted 2-propenoic acid derivatives which possess a fullysubstituted nitrogen on the enamide are not known and the viability ofthe standard preparative sequence for the enamide is unclear. Ingeneral, the majority of enamides that have undergone asymmetrichydrogenation possess a hydrogen substituent on the nitrogen of theenamide. Thus the efficacy of asymmetric catalysts for the hydrogenationof lactam-substituted 2-propenoic acid derivatives is also unclear.

[0004] U.S. Pat. No. 4,696,943 discloses the synthesis of singleenantiomer lactam-substituted propanoic acid derivatives useful aspharmaceutical agents for various conditions. However, these compoundswere prepared by a cyclization reaction and not by the asymmetrichydrogenation of an enamide.

[0005] In light of the above, it would be desirable to produce singleenantiomer lactam-substituted propanoic acid derivatives useful aspharmaceutical compounds.

SUMMARY OF THE INVENTION

[0006] The present invention relates to highly enantiomerically purelactam-substituted propanoic acid derivatives and methods of making andusing therefor. The invention involves a multi-step synthesis to producethe lactam compounds. In one step of the reaction sequence, asymmetrichydrogenation of a lactam-enamide was performed to produce anintermediate that can ultimately be converted to a series ofpharmaceutical compounds. The invention also contemplates the in situsynthesis of an intermediate of the multi-step synthesis, which provideseconomic advantages to the overall synthesis of the lactam compounds.

[0007] Additional advantages of the invention will be set forth in partin the description that follows, and in part will be apparent from thedescription or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention may be understood more readily by referenceto the following detailed description of aspects of the invention andthe Examples included therein.

[0009] Before the present compositions of matter and methods aredisclosed and described, it is to be understood that this invention isnot limited to specific synthetic methods or to particular formulations,and, as such, may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularaspects only and is not intended to be limiting.

[0010] The singular forms a, an, and the include plural referents unlessthe context clearly dictates otherwise.

[0011] Optional or optionally means that the subsequently describedevent or circumstances may or may not occur, and that the descriptionincluded instances where said event or circumstance occurs and instanceswhere it does not.

[0012] The term “alkyl group” may include straight- or branched-chain,aliphatic hydrocarbon radicals containing up to about 20 carbon atomsand may be substituted, for example, with one to three groups selectedfrom C₁-C₆-alkoxy, cyano, C₂-C₆-alkoxycarbonyl, C₂-C₆ alkanoyloxy,hydroxy, aryl and halogen. The terms “C₁-C₆-alkoxy,”“C₂-C₆-alkoxycarbonyl,” and “C₂-C₆ -alkanoyloxy” are used to denoteradicals corresponding to the structures —OR, —CO₂R, and —OCOR,respectively, wherein R is C₁-C₆-alkyl or substituted C₁-C₆-alkyl.

[0013] The term “cycloalkyl” is used to denote a saturated, carbocyclichydrocarbon. The term “substituted cycloalkyl” is a cycloalkyl groupsubstituted with one or more of the groups described above.

[0014] The term “aryl group” may include phenyl, naphthyl, oranthracenyl and phenyl, naphthyl, or anthracenyl substituted with one tothree substituents selected from C₁-C₆-alkyl, substituted C₁-C₆-alkyl,C₆-C₁₀ aryl, substituted C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy,cyano, C₁-C₆-alkanoyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl,trifluoromethyl, hydroxy, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino and—OR, SR, —SO₂R, —NHSO₂R and —NHCO₂R, wherein R is phenyl, naphthyl, orphenyl or naphthly substituted with one to three groups selected fromC₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy and halogen.

[0015] The term “heteroaryl group” includes a 5- or 6- membered aromaticring containing one to three heteroatoms selected from oxygen, sulfurand nitrogen. Examples of such heteroaryl groups are thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and thelike. The heteroaryl group may be substituted, for example, with up tothree groups such as C₁-C₆-alkyl, C₁-C₆-alkoxy, substituted C₁-C₆-alkyl,halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy, C₂-C₆-alkoxycarbonyland C₂-C₆-alkanoylamino. The heteroaryl group also may be substitutedwith a fused ring system, e.g., a benzo or naphtho residue, which may beunsubstituted or substituted, for example, with up to three of thegroups set forth in the preceding sentence.

[0016] Reference will now be made in detail to the present aspects ofthe invention. Wherever possible, the same reference numbers and lettersare used throughout the various formulas in the invention to refer tothe same or like parts.

[0017] The present invention relates to the synthesis ofenantiomerically pure lactam-substituted propanoic acid derivatives andmethods of making and using therefor. A reaction scheme that depicts ageneral sequence of reaction steps to produce the compounds of theinvention is shown in Scheme 1.

[0018] The first step depicted in Scheme 1 involves the reaction (i.e.,condensation) between a compound having the formula I

[0019] with glyoxylic acid, wherein R¹ is hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl, and

[0020] n is from 0 to 5,

[0021] to produce a compound having the formula II.

[0022] The condensation reaction between lactam I and glyoxylic acid isgenerally conducted in a solvent. Examples of useful solvents include,but are not limited to, aliphatic hydrocarbons such as hexane, heptane,octane and the like, aromatic hydrocarbons such as toluene, xylenes, andthe like, cyclic or acyclic ethers such as diethyl ether, tert-butylmethyl ether, diisopropyl ether, tetrahydrofuran and the like, or polaraprotic solvents such as dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone and the like. The amount of glyoxylic acid relativeto the amount of compound I can vary. In one aspect, the glyoxylic acidis present in the amount from 0.8 to 2 equivalents per 1.0 equivalent ofthe compound having the formula I. The condensation reaction isgenerally run between ambient temperature and the boiling point of thelowest boiling component of the mixture.

[0023] The second step depicted in Scheme 1 involves converting compoundII to a compound having the formula III

[0024] wherein R¹, R³, and R⁴ are, independently, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or a substituted or unsubstituted C₄to C₂₀ heteroaryl group, wherein R¹ can also be hydrogen, and n is from0 to 5.

[0025] The second step generally involves reacting a compound having theformula II with an alcohol comprising an alkyl alcohol, an aryl alcohol,or a heteroaryl alcohol, wherein the alkyl alcohol is substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl or substitutedor unsubstituted C₃ to C₈ cycloalkyl; the aryl alcohol is substituted orunsubstituted C₆ to C₂₀ aryl; and the heteroaryl alcohol is substitutedor unsubstituted C₄ to C₂₀ heteroaryl, wherein the heteroatom is oxygen,nitrogen, or sulfur. Although R³ and R⁴ need not be the same group, theycan be derived from the same alcohol. In one aspect, the alcohol is a C₁to C₅ alcohol, preferably methanol or ethanol. The amount of alcoholthat is used can vary. In one aspect, the alcohol is present in theamount from 2.0 to 5.0 equivalents per 1.0 equivalent of the compoundhaving the formula II.

[0026] In another aspect, the second step is generally conducted underdehydrating conditions using acid catalysis. For example, the use of adehydrating agent such as a trialkyl orthoformate or the physicalremoval of water from the reaction mixture via an azeotropicdistillation are useful in the present invention. When a dehydratingagent is used, the amount of dehydrating agent used relative to theamount of compound II is generally between 2 and 5 molar equivalents. Ingeneral, the alcohol can be used as the reaction solvent for thepreparation of compound III; however, co-solvents can be used. Examplesof co-solvents useful in the present invention include, but are notlimited to, aliphatic hydrocarbons such as hexane, heptane, octane andthe like, aromatic hydrocarbons such as toluene, xylenes, and the like.A preferable co-solvent is toluene or xylene. The second step isgenerally performed at a temperature between ambient temperature and theboiling point of the lowest boiling component of the reaction mixture.In one aspect, the reaction is performed between 20° C. and 120° C.

[0027] The compounds produced in steps 1 and 2 can be represented by thegeneral formula XI

[0028] wherein R¹, R³, and R⁴ are, independently, hydrogen, asubstituted or unsubstituted, branched or straight chain C₁ to C₂₀ alkylgroup; a substituted or unsubstituted C₃ to C₈ cycloalkyl group; asubstituted or unsubstituted C₆ to C₂₀ aryl group; or substituted orunsubstituted C₄ to C₂₀ heteroaryl group, and n is from 0 to 5. In oneaspect, n is 2. In another aspect, R¹, R³, and R⁴ are hydrogen and n is2. In a further aspect, R¹ is hydrogen, R³ and R⁴ are methyl, and n is2.

[0029] The third step in Scheme 1 involves converting compound III tothe halogenated lactam compound having the formula IV

[0030] wherein R¹ and R³ are, independently, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl, whereinR¹ can also be hydrogen, X is fluoride, chloride, bromide, or iodide,and n is from 0 to 5.

[0031] The third step generally involves reacting compound III with aphosphorous trihalide having the formula PX₃, wherein X is fluoro,chloro, bromo, or iodo. In one aspect of the invention, the phosphoroustrihalide is phosphorous trichloride or phosphorous tribromide. Theamount of the phosphorus trihalide is generally between 0.8 and 2.0molar equivalents based on compound III. Typically, the reaction isperformed in an inert solvent including, but not limited to, aliphatichydrocarbons such as hexane, heptane, octane and the like, aromatichydrocarbons such as toluene, xylenes, and the like, and halogenatedhydrocarbons such as dichloromethane, dichloroethane,tetrachloroethylene, chlorobenzene, and the like. The third step isgenerally performed at a temperature between ambient temperature and theboiling point of the lowest boiling component of the reaction mixturefor a time necessary to consume the majority of compound III. In oneaspect, the reaction solvent is toluene or xylene and the reactiontemperature is between 40° C. and 80° C.

[0032] The fourth step in Scheme 1 involves converting compound IV to acompound having the formula V

[0033] wherein R¹ and R³ are, independently, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl, whereinR¹ can also be hydrogen,

[0034] R⁶ is substituted or unsubstituted, branched or straight chain C₁to C₂₀ alkyl or substituted or unsubstituted C₃ to C₈ cycloalkyl, and

[0035] n is from 0 to 5. In one aspect, n is 2 and R¹ is hydrogen. Inanother aspect of the invention, R³ is methyl or ethyl. In a furtheraspect, R⁶ is methyl or ethyl.

[0036] The fourth step is an Arbuzov reaction comprising reacting acompound having the formula IV with a phosphite having the formulaP(OR⁶)₃, wherein R⁶ is substituted or unsubstituted, branched orstraight chain C₁ to C₂₀ alkyl or substituted or unsubstituted C₃ to C₈cycloalkyl. In one aspect, the phosphite is trimethyl phosphite ortriethyl phosphite. In another aspect of the invention, compound IV isthe chloro or bromo compound (X═Cl or Br). The amount of the phosphiteis generally between 0.8 and 1.2 molar equivalents based on compound IV.The reaction is optionally conducted in the presence of a solventincluding, but not limited to, aliphatic hydrocarbons such as hexane,heptane, octane and the like, aromatic hydrocarbons such as toluene,xylenes, and the like, cyclic or acyclic ethers such as tert-butylmethyl ether, diisopropyl ether, tetrahydrofuran and the like,halogenated hydrocarbons such as dichloromethane, dichloroethane,tetrachloroethylene, chlorobenzene and the like, or polar aproticsolvents such as dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone and the like. The reaction is generally performed ata temperature between ambient temperature and the boiling point of thelowest boiling component of the reaction mixture for a time necessary toconsume the majority of compound IV. In one aspect, the solvent istoluene or xylene and the reaction is performed between 40° C. and 100°C.

[0037] The fifth step in Scheme 1 involves converting compound V to acompound having the formula VI

[0038] wherein R¹, R², and R³ are, independently, hydrogen, substitutedor unsubstituted, branched or straight chain C₁ to C₂₀ alkyl;substituted or unsubstituted C₃ to C₈ cycloalkyl; substituted orunsubstituted C₆ to C₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀heteroaryl, and n is from 0 to 5. In one aspect, n is 2 and R¹ ishydrogen. In another aspect, R² and R³ are methyl. In a further aspect,R² is methyl and R³ is ethyl.

[0039] The fifth step of the sequence is a Homer-Emmons Wittig reactionbetween phosphonate compound V and a n aldehyde having the formulaHC(O)R² to afford enamide VI. In one aspect of the invention, thealdehyde is acetaldehyde. The reaction generally involves the use of abase. For example, the base can be a moderately strong non-hydroxidebase with a pKa of about 13 or above. Examples of non-hydroxide basesinclude, but are not limited to, amidine bases such as1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or guanidine bases such astetramethylguanidine (TMG). The amount of base is usually between 1.0and 2.0 molar equivalents based on compound V, and the amount ofaldehyde is generally between 0.8 and 1.5 molar equivalents basedcompound V.

[0040] The reaction to produce compound VI is generally conducted in thepresence of a solvent. Solvents useful in the reaction include, but arenot limited to, aliphatic hydrocarbons such as hexane, heptane, octaneand the like, aromatic hydrocarbons such as toluene, xylenes, and thelike, cyclic or acyclic ethers such as tert-butyl methyl ether,diisopropyl ether, tetrahydrofuran and the like, halogenatedhydrocarbons such as dichloromethane, dichloroethane,tetrachloroethylene, chlorobenzene and the like, or polar aproticsolvents such as dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone and the like. The reaction is generally performed ata temperature between −80° C. and the boiling point of the lowestboiling component of the reaction mixture for a time necessary tolargely consume compound V. In one aspect of the invention, the reactionis performed in toluene or xylene at a temperature of 0° C. to 50° C.

[0041] The invention also contemplates producing compound VI fromcompound III in situ. The term “in situ” is defined herein as performingtwo or more reaction sequences without isolating any of theintermediates that are produced during the reaction sequence. One aspectof the invention involves a method for producing the compound VI insitu, comprising

[0042] (a) reacting a compound having the formula III

[0043]  wherein R³ and R⁴ are a substituted or unsubstituted, branchedor straight chain C₁ to C₂₀ alkyl group; a substituted or unsubstitutedC₃ to C₈ cycloalkyl group; a substituted or unsubstituted C₆ to C₂₀ arylgroup; or substituted or unsubstituted C₄ to C₂₀ heteroaryl group,wherein R¹ can also be hydrogen,

[0044] with PX₃, wherein X is fluoride, chloride, bromide, or iodide, toproduce a halogenated lactam;

[0045] (b) reacting the halogenated lactam produced in step (a) with aphosphite having the formula P(OR⁶)₃, wherein R⁶ is substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl or substitutedor unsubstituted C₃ to C₈ cycloalkyl, to produce a phosphonated lactam;and

[0046] (c) reacting the phosphonated lactam produced in step (b) with analdehyde having the formula HC(O)R², wherein R² is hydrogen, substitutedor unsubstituted, branched or straight chain C₁ to C₂₀ alkyl;substituted or unsubstituted C₃ to C₈ cycloalkyl; substituted orunsubstituted C₆ to C₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀heteroaryl,

[0047] in the presence of a base,

[0048] wherein steps (a), (b), and (c) are performed in situ. In thisaspect of the invention, compounds IV and V are not isolated. The insitu preparation of compound VI would not have been expected due to theincompatibility of several of the reagents used in the in situ process.In addition, there is an economic advantage to combining multiplereaction steps without having to isolate each of compound that isproduced.

[0049] The sixth step in Scheme 1 involves converting compound VI to acompound having the formula VII

[0050] wherein R¹, R², and R³ are, independently, hydrogen, asubstituted or unsubstituted, branched or straight chain C₁ to C₂₀ alkylgroup; a substituted or unsubstituted C₃ to C₈ cycloalkyl group; asubstituted or unsubstituted C₆ to C₂₀ aryl group; or substituted orunsubstituted C₄ to C₂₀ heteroaryl group,

[0051] n is from 0 to 5,and

[0052] the stereochemistry at carbon a is substantially R or S.

[0053] The term “substantially R or S” refers to the enantiomeric purityof the aformentioned compound, which is measured by the enantiomericexcess of this material. The enantiomeric excess (ee) is defined as thepercent of one enantiomer of the mixture minus the percent of the otherenantiomer. “Substantially R” indicates an ee of 90% or greater with theR enantiomer the major enantiomer, whilst “substantially S” indicates anee of 90% or greater with the S enantiomer the major enantiomer. In oneaspect of the invention, the stereochemistry at carbon a issubstantially S. In another aspect of the invention, the stereochemistryat carbon a is substantially R.

[0054] In other aspects of the invention, the heteroatom of theheteroaryl group in compound VII is oxygen, sulfur, or nitrogen, and thesubstituent on the substituted alkyl, aryl, or heteroaryl groupcomprises alkyl, aryl, hydroxy, alkoxy, fluoro, chloro, bromo, iodo,nitro, cyano, or an ester; R² and R³ are independently selected frommethyl or ethyl; R¹ is hydrogen, R² is methyl, R₃ is methyl or ethyl;and n is 2.

[0055] The conversion of compound VI to compound VII compriseshydrogenating compound VI with hydrogen in the presence of a catalystcomprised of a chiral ligand/metal complex to asymmetrically hydrogenatethe carbon-carbon double bond of compound VI. The term “hydrogenate”generally refers to reacting a carbon-carbon double or triple bond withhydrogen to reduce the degree of unsaturation. For example, thecarbon-carbon double bond of compound VI is hydrogenated to produce acarbon-carbon single bond. Here, the degree of unsaturation has beenreduced by one. Referring to Scheme 2, hydrogen can be added to side b(front side) or c (back side) of the carbon-carbon double bond ofcompound VII. The stereochemistry at carbon a of compound VII will bedetermined by which side of the carbon-carbon double bond hydrogenapproaches. The term “asymmetrically hydrogenating” refers to theaddition of hydrogen to a particular side or face (b or c) of thecarbon-carbon double bond of compound VII in preference to the otherside. The degree of asymmetric hydrogenation is described by theenantiomeric excess of the asymmetric hydrogenation product.

[0056] The asymmetric hydrogenation of compound VI involves the use of achiral ligand/metal complex. The chiral ligand/metal complex is composedof a chiral ligand and a metal, where the metal is either chemicallybonded to the chiral ligand or the metal is coordinated to the chiralligand. Any chiral ligand/metal complex known in the art can be used toasymmetrically hydrogenate compound VI. For example, the chiralligand/metal complexes disclosed in Ohkuma et al. in CatalyticAsymmetric Synthesis, 2^(nd) Ed, Wiley-VCH, 2000, pages 1-17, which isincorporated by reference in its entirety, are useful in the presentinvention.

[0057] In one aspect of the invention, the chiral ligand of the chiralligand/metal complex comprises the substantially pure enantiomer ordiastereomer of 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane;2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;1,2-bis-2,5-dialkylphospholano(benzene);1,2-bis-2,5-dialkylphospholano(ethane); 2,3-bis-(diphenylphosphino)butane; or2-diphenylphosphinomethyl-4-diphenylphophino-1-t-butoxycarbonylpyrrolidine.

[0058] In another aspect of the invention, the chiral ligand of thechiral ligand/metal complex comprises a substantially enantiomericallypure bis-phosphine compound comprising one phosphine residue havingthree phosphorus-carbon bonds and the other having two phosphorus-carbonbonds and one phosphorus-nitrogen bond. In one aspect of the invention,the chiral ligand of the chiral ligand/metal complex comprises aphosphine or a bis-phosphine compound and the metal of the chiralligand/metal complex comprises rhodium, ruthenium, or iridium.

[0059] Examples of substantially enantiomerically pure bis-phosphinecompounds, e.g., an enantiomeric excess of 90% or greater, includephosphinometallocenyl-aminophosphines having the general formulas IX andX (the enantiomer of IX):

[0060] where R⁷,R⁸, R⁹, R¹⁰, R¹¹, and R¹²are, independently, hydrogen,substituted or unsubstituted branched or straight chain C₁ to C₂₀ alkyl,substituted or unsubstituted C₃ to C₈ cycloalkyl, substituted orunsubstituted C₆ to C₂₀ aryl, and substituted or unsubstituted C₄ to C₂₀heteroaryl, where the heteroatoms are chosen from sulfur, nitrogen, oroxygen, provided R¹² is not hydrogen;

[0061] a is from 0 and 3;

[0062] b is from 0 and 5; and

[0063] M is a Group IV to Group VIII metal. The synthesis of the chiralligands having the formulas IX and X is disclosed in U.S. ProvisionalApplication Nos. 60/236,564 and 60/264,411, both of which areincorporated by reference in their entireties.

[0064] The alkyl groups that may be represented by each of R⁷, R⁸, R⁹,R¹⁰, R¹¹, and R¹² in formulas IX and X may be straight- orbranched-chain, aliphatic hydrocarbon radicals containing up to about 20carbon atoms and may be substituted, for example, with one to threegroups selected from C₁-C₆-alkoxy, cyano, C₂-C₆-alkoxycarbonyl, C₂-C₆alkanoyloxy, hydroxy, aryl and halogen. The terms “C₁-C₆-alkoxy,”“C₂-C₆-alkoxycarbonyl,” and “C₂-C₆-alkanoyloxy” are used to denoteradicals corresponding to the structures —OR¹³, —CO₂R¹³, and —OCOR¹³,respectively, wherein R¹³ is C₁-C₆-alkyl or substituted C₁-C₆-alkyl. Theterm “C₃-C₈-cycloalkyl” is used to denote a saturated, carbocyclichydrocarbon radical having three to eight carbon atoms.

[0065] The aryl groups for each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² informulas IX and X may include phenyl, naphthyl, or anthracenyl andphenyl, naphthyl, or anthracenyl substituted with one to threesubstituents selected from C₁-C₆-alkyl, substituted C₁-C₆-alkyl, C₆-C₁₀aryl, substituted C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano,C₁-C₆-alkanoyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl,trifluoromethyl, hydroxy, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino and—O—R ⁴, S—R¹⁴,—SO₂—R¹⁴, —NHSO₂R¹⁴ and —NHCO₂R¹⁴, wherein R¹⁴ is phenyl,naphthyl, or phenyl or naphthly substituted with one to three groupsselected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy and halogen.

[0066] The heteroaryl radicals include a 5- or 6- membered aromatic ringcontaining one to three heteroatoms selected from oxygen, sulfur andnitrogen. Examples of such heteroaryl groups are thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and thelike. The heteroaryl radicals may be substituted, for example, with upto three groups such as C₁-C₆-alkyl, C₁-C₆-alkoxy, substitutedC₁-C₆-alkyl, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy,C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino. The heteroaryl radicalsalso may be substituted with a fused ring system, e.g., a benzo ornaphtho residue, which may be unsubstituted or substituted, for example,with up to three of the groups set forth in the preceding sentence. Theterm “halogen” is used to include fluorine, chlorine, bromine, andiodine.

[0067] In one aspect of the invention, when the chiral ligand is acompound having the formula IX or X, R¹² is C₁ to C₆ alkyl (e.g.,methyl); R⁷ is hydrogen or C₁ to C₆ alkyl (e.g., methyl); R⁸ is aryl(e.g., phenyl), ethyl, isopropyl, or cyclohexyl; R⁹ is aryl (e.g.,phenyl); R¹⁰ and R¹¹ are hydrogen; and M is iron, ruthenium, or osmium.

[0068] The chiral ligand/metal complex can be prepared and isolated, or,in the alternative, it can be prepared in situ. The preparation ofchiral ligand/metal complexes is generally known in the art. The chiralligand to metal molar ratio can be from 0.5:1 to 5:1, preferably from1:1 to 1.5:1. The amount of chiral ligand/metal complex may vary between0.0005 and 0.5 equivalents based on compound VI, with more catalystleading to a faster reaction.

[0069] The hydrogenation reaction is conducted under an atmosphere ofhydrogen, but other materials that are inert to the reaction conditionsmay also be present. The reaction can be run at atmospheric pressure orat elevated pressure of from 0.5 to 200 atmospheres. The reactiontemperature can be varied to modify the rate of conversion, usuallybetween ambient temperature and the boiling point (or apparent boilingpoint at elevated pressure) of the lowest boiling component of thereaction mixture. In one aspect of the invention, the hydrogenation stepis conducted at from −20° C. to 100° C. The reaction is usually run inthe presence of a solvent. Examples of useful solvents include, but arenot limited to, aliphatic hydrocarbons such as hexane, heptane, octaneand the like, aromatic hydrocarbons such as toluene, xylenes, and thelike, cyclic or acyclic ethers such as tert-butyl methyl ether,diisopropyl ether, tetrahydrofuran and the like, dialkyl ketones such asacetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone andthe like, or polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like.

[0070] Compounds having the formula VII can be converted to the amidecompounds VIII

[0071] wherein R¹ and R² are, independently, hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl,

[0072] n is from 0 to 5, and

[0073] the stereochemistry at carbon a is substantially R or S,

[0074] comprising reacting a compound having the formula VII with NH₄OH.

[0075] The amount of NH₄OH can vary, wherein from 1 to 10 equivalents ofNH₄OH per 1.0 equivalent of the compound having the formula VII can beused. The reaction is generally performed in water optionally in thepresence of a water-miscible organic solvent, including, but not limitedto, a lower alcohol such as methanol or ethanol, THF, DMF, or DMSO. Thereaction is preferably performed in water as the sole solvent. Thereaction temperature can also vary, however; the reaction is typicallyperformed from 0° C. to 50° C. The compounds having the formula VIII canbe used to treat a number of different maladies, some of which aredisclosed in U.S. Pat. No. 4,696,943, which is incorporated by referencein its entirety.

[0076] In summary, the invention provides lactam-substituted propanoicacid derivatives that are useful precursors to enantiomerically-purelactam-substituted propanoic acid derivatives. The invention provides anefficient method for making the lactam-substituted propanoic acidderivatives as well as the enantiomerically enriched compounds, whichwill ultimately be used to produce pharmaceutical compounds.

[0077] Throughout this application, where publications are referenced,the disclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

EXAMPLES

[0078] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow the compositions of matter and methods claimed herein are made andevaluated, and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.) but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are by weight, temperature is in °C or is at roomtemperature and pressure is at or near atmospheric.

Example 1 Preparation of Methyl 2-(2-Pyrrolidino)Propanoate

[0079] Step 1: Preparation of Hydroxy-acid 2a (formula II, n=2,R¹=R³=R⁴=H):

[0080] Glyoxylic acid monohydrate (20.2 g; 220 mmol; 1.1 equiv) wasslurried in 200 mL of diethyl ether. Pyrrolidinone (15.2 mL; 200 mmol)was added and the resulting mixture was stirred at ambient temperaturefor two days to afford a white precipitate. The precipitate was isolatedby filtration, washed with ether, and air-dried to afford 36.06 g (99%)of hydroxy-acid 2a. ¹H NMR (DMSO-d₆)δ5.55 (s, 1 H);3.5-3.3 (m, 2H); 3.36(s, 3H); 2.46 (m, 2H); 2.07 (m, 2H).

[0081] Step 2: Preparation of Ether-ester 3a (formula III, n=2R¹=H,R³=R⁴=Me):

[0082] Hydroxy-acid 2a (25.3 g; 160 mmol) was dissolved in methanol (370mL), cooled in ice-water, and treated with concentrated sulfuric acid(5.0 mL; 0.093 mmol; 0.57 molar equiv). The reaction mixture was allowedto warm to ambient temperature and allowed to stir for 5 days. Solidsodium bicarbonate (17.1 g; 203 mmol; 1.27 equiv) was added and thereaction mixture was stirred for 30 min. The reaction mixture wasfiltered and the filtrate was concentrated. The resulting material wasdiluted with water (25 mL) and extracted with ethyl acetate (2×50 mL).The combined extracts were dried with magnesium sulfate and the solventwas evaporated to afford 22.84 g (76%) of 3a. ¹H NMR(CDCl₃)δ5.64(s, 1H);3.78(s, 3H);3.40(m, 1H);3.16(m, 1H);2.24(m, 2H);1.90(m, 2H).

[0083] Steps 3 and 4: Preparation of Phosphonate Ester 5a (formula V,n=2, R¹=H, R³=R⁶=Me):

[0084] Ether-ester 3a (9.36 g; 50 mmol) was dissolved in 50 mL oftoluene. The reaction mixture was heated to 70° C. and phosphorustrichloride (4.36 mL; 50 mmol; 1.0 equiv) was added. The reactionmixture was heated at 70° C. for 18 h to afford chloride 4a (formula IV,X=Cl, R³=Me). Trimethyl phosphite (5.9 mL; 50 mmol; 1.0 equiv) was thenadded. The resulting mixture was heated for 36 h and then cooled toambient temperature. The volatiles were stripped at reduced pressure andthe remaining material was dissolved in 100 mL of ethyl acetate. Themixture was washed with saturated aqueous sodium bicarbonate (2×25 mL),and the resulting aqueous solution was back-extracted three times withethyl acetate. The combined ethyl acetate solution was dried withmagnesium sulfate and concentrated to afford 4.35 g (33%) of phosphonate5a. ¹H NMR (CDCl₃)δ5.46(d, 1H, J_(P-H)=24.72 Hz);3.84(d, 3H,J_(P-H)=10.99 Hz); 3.80(s, 3H);3.78(d, 3H, J_(P-H)=11.26 Hz)3.8(m, 1H);3.66 (m, 1H); 2.42 (m, 2H);2.08(m, 2 H).

[0085] Step 5: Preparation of Enamide 6a (formula VI, n=2, R¹=H,R²=R³=Me):

[0086] Phosphonate 5a (2.65 g; 10 mmol) was dissolved in 10 mL oftetrahydrofuran. The mixture was cooled to −78° C. andtetramethylguanidine (2.88 mL; 15 mmol; 1.5 equiv) was added. Thereaction mixture was stirred for 15 min and acetaldehyde (0.84 mL; 15mmol; 1.5 equiv) was added. The resulting mixture was stirred at −78° C.for 1 h and then warmed to ambient temperature and stirred overnight.The volatiles were evaporated at reduced pressure and water (10 mL) wasadded. The mixture was extracted three times with ethyl acetate and thecombined extracts were dried with magnesium sulfate and concentrated.The crude product was filtered through a pad of flash silica gel andeluted with ethyl acetate to afford 1.37 g (75%) of 6a as a mixture of Eand Z isomers.

[0087] E-6a: ¹H NMR (CDCl₃)δ7.05 (q, 1H, J=7.14 Hz); 3.74 (s,3H);3.55(t, 2H, J=6.86 Hz);2.46(m, 2H);2.15(m, 2H);1.77 (d, 3H, J=7.19Hz).

[0088] Z-6a: ¹H NMR (CDCl₃) 8 5.99 (q, 1H, J=7.42 Hz); 3.78 (s, 3H);2.02 (d, 3H, J=7.42 Hz).

[0089] Step 6: Hydrogenation of Enamide 6a to afford ester 7a (formulaVII, n=2, R¹=H, R²=R³=Me) using Ligand 9a (formula IX, R¹²=R⁷=Me,R⁸=R⁹=Ph, a=b=0,M=Fe):

[0090] A Fischer-Porter tube was charged with ligand 9a (22 mg, 0.036mmol; 0.064 equiv) and anhydrous THF (4.0 mL) under an argon atmosphere.Argon was bubbled through the solution for 20 minutes before theaddition of bis(1,5-cyclooctadienyl)rhodium trifluoromethanesulfonate(12 mg; 0.026 mmol; 0.047 equiv). The solution was stirred at 25° C. for5 minutes or until all bis(1,5-cyclooctadienyl)rhodiumtrifluoromethanesulfonate had dissolved. Enamide 5a (100 mg, 0.55 mmol)was added via syringe. The vessel was capped and pressurized to 40 psiH₂. After 18 hours, the mixture was diluted with hexane (4.0 mL) andfiltered through silica gel to remove the catalyst. The product 7a wasisolated as an oil (99% yield, 96.2% ee as determined by chiral GC).

[0091]¹H NMR (CDCl₃δ4.71-4.65 (m, 1H), 3.71 (s, 3H), 3.55-3.47 (m, 1H),3.38-3.30 (m, 1H), 2.45-2.40 (t, J=8.4 Hz, 2H), 2.12-1.97 (m, 3H),1.74-1.64 (m, 1H), 0.94-0.89 (t, J=7.5 Hz, 3H). Chiral GC analysis[Cyclosil-B (J&W Scientific), 40° C. for 4 min to 175° C. at 70° C. min,hold at 175° C. for 12 minutes: t_(R)=23.19 (major enantiomer),t_(R)=23.24 (minor enantiomer)].

Example 2

[0092] In Situ Preparation of Compound VI (n=2 R¹=H, R²=R³=Me):

[0093] Ether-ester 3a (9.36 g; 50 mmol) was dissolved in 25 mL oftoluene. The reaction mixture was heated to 50° C. and phosphorustrichloride (4.4 mL; 50 mmol; 1.0 equiv) was added and the mixture washeld at 50° C. for 16 h. The reaction mixture was cooled to ambienttemperature and sodium bicarbonate (10.5 g; 125 mmol; 2.5 equiv) wasadded. The mixture was stirred for 15 min, filtered, and the volatileswere stripped. The solution was reconstituted by the addition of toluene(25 mL) and heated to 70° C. Trimethyl phosphite (6.5 mL; 55 mmol; 1.1equiv) was added and the reaction mixture was heated at 70° C. for 24 hto completely consume 4a. The mixture was then cooled to 2° C. andacetaldehyde (4.2 mL; 75 mmol; 1.5 equiv) was added.Tetramethylguanidine (9.41 mL; 75 mmol; 1.5 equiv) was then added slowlydropwise with an attendant exotherm to 8.5° C. The reaction mixture wasallowed to warm to ambient temperature and stirred overnight to consumephosphonate 5a. Water (15 mL) was added and the layers were separated.The aqueous layer was extracted with ethyl acetate (2×15 mL) and theorganic solutions were dried and concentrated to afford a total of 9.23g of crude 6a. This material was filtered through a pad of flash silicagel and eluted with ethyl acetate to afford 7.13 g (78% overall from 3a)of 6a.

Example 3 Preparation of Ethyl 2-(2-Pyrrolidino)propanoate

[0094] Step 2: Preparation of Ether-ester 3b (formula III, n=2, R¹=H,R³=R⁴=Et):

[0095] Hydroxy-acid 2a (7.96 g; 50 mmol) was dissolved in ethanol (25mL), and triethyl orthoformate (18.3 mL; 110 mmol; 2.2 equiv) was added.p-Toluenesulfonic acid (0.48 g; 2.5 mmol; 0.05 equiv) was added and thereaction mixture was heated to 60° C. for 24 h. Solid sodium bicarbonate(0.50 g; 6 mmol; 0.12 equiv) was added and the reaction mixture wasstirred for 15 min. The volatiles were evaporated at reduced pressureand the remaining material was dissolved in 1:1 toluene:ethyl acetate(25 mL), filtered, and concentrated to afford 10.25 g (95%) of 3b.

[0096]¹H NMR (CDCl₃)δ5.72 (s, 1 H); 4.24 (q, 2H, J=7.14 Hz); 3.57 (q,2H, J=6.87 Hz); 3.5-3.3 (m, 2H); 2.47 (t, 2H, J=7.42 Hz); 2.06 (m(5),2H, J=7.42 Hz); 1.29 (t, 3H, J=7.14 Hz); 1.25 (t, 3H, J=6.87 Hz).

[0097] Steps 3 and 4: Preparation of Phosphonate Ester 5b (formula V,n=2, R¹=H, R³=Et, R=Me):

[0098] Ether-ester 3b (5.38 g; 25 mmol) was dissolved in 12.5 mL oftoluene. The reaction mixture was heated to 50° C. and phosphorustrichloride (2.2 mL; 25 mmol; 1.0 equiv) was added. The reaction mixturewas heated at 50° C. for 12 h and then at 70° C. for 24 h to completelyconsume 3b and afford chloride 4b (formula IV, X =Cl, R³=Et). Solidsodium bicarbonate (5.25 g; 62.5 mmol; 2.5 equiv) was added and themixture was stirred for 15 min. The reaction mixture was then filteredand concentrated at reduced pressure. Toluene (12.5 mL) was added andthe reaction mixture was heated to 70° C. where trimethyl phosphite(3.24 mL; 25 mmol; 1.0 equiv) was added. The resulting mixture washeated at 70° C. for 24 h and then cooled to ambient temperature. Thevolatiles were evaporated at reduced pressure to afford 7.00 g (99%) ofphosphonate 5b, which was used without further purification.

[0099]¹H NMR (CDCl₃)δ5.43 (d, 1H, J_(P-H)=24.72 Hz); 4.25 (q, 2H, J=7.14Hz); 3.84 (d, 3H, J_(P-H)=10.99 Hz); 3.77 (d, 3H, J_(P-H)=10.99 Hz) 3.8(m, 1H); 3.66 (m, 3H); 2.40 (m, 2H); 2.06 (m, 2 H); 1.29 (t, 3H, J=7.14Hz).

[0100] Step 5: Preparation of Enamide 6b (formula VI, n=2, R¹=H, R³ =Et,R²=Me):

[0101] Phosphonate 5b (7.00 g; 25 mmol) was dissolved in 12.5 mL oftoluene. The mixture was cooled to 2° C. and acetaldehyde (2.1 mL; 37.5mmol; 1.5 equiv) was added. Tetramethylguanidine (3.5 mL; 27.5 mmol; 1.1equiv) was added dropwise accompanied by a moderate exotherm. Thereaction mixture was allowed to warm to ambient temperature and stirredovernight and then heated to 50° C. for 12 h to completely consume 5b.The reaction mixture was diluted with 3 N HCl (10 mL) and the layerswere separated. The aqueous layer was extracted twice with ethyl acetateand the combined organic solution was dried with magnesium sulfate andconcentrated. The crude product was filtered through a pad of flashsilica gel and eluted with ethyl acetate to afford 2.85 g (58%) of 6b asa mixture of E and Z isomers.

[0102] E-6b: ¹H NMR (CDCl₃)δ7.05 (q, 1H, J=7.14 Hz); 4.20 (q, 2H, J=7.14Hz); 3.55 (t, 2H, J=7.14 Hz); 2.48 (t, 2H, J=7.69 Hz); 2.15 (m(5), 2H,J=7.6 Hz); 1.77 (d, 3H, J=7.14 Hz); 1.28 (t, 3H, J=7.14 Hz).

[0103] Z-6b: ¹H NMR (CDCl₃)δ6.0 (q, 1H); 3.78 (s, 3H); 4.12 (q, 2H);1.95 (d, 3H).

[0104] Step 6: Hydrogenation of Enamide 6b to afford ester 7b (formulaVII, n=1 R¹=H, R³=Et, R²=Me) using Ligand 10a (formula X, R¹²=R⁷ =Me,R⁸=R⁹=Ph, a=b=0, M=Fe): Bis(1,5-cyclooctadienyl)rhodiumtrifluoromethanesulfonate (5 μmol, 2.3 mg) was placed into a reactionvessel and purged with argon for 20 min. A solution of 10a (6 μmol, 3.7mg) in anhydrous THF (2.0 mL) was degassed with Ar for 20 minutes, thenadded via cannula to the bis(1,5-cyclooctadienyl)rhodiumtrifluoromethanesulfonate. This solution was stirred at 25° C. under Arfor 20 minutes. A solution of enamide 6b (0.5 mmol) in anhydrous THF(2.0 mL) was degassed with Ar for 20 minutes, then added to the catalystsolution via cannula. The solution was then flushed with H₂ andpressurized to 20 psig H₂. A sample was taken after 1 hour and analyzedfor enantiomeric excess using standard chiral gas chromatography. 7b wasformed in 95.0% ee with >99% conversion. Chiral GC analysis [Cyclosil-B(J&W Scientific), 30 m×0.25 mm ID, film thickness 0.25 μm, 60-140° C.40° C./min, 140° C. 30 min, 20 psig He: t_(R)(minor enantiomer) 26.26min, t_(R)(major enantiomer) 26.82 min.

Example 4 Preparation of Amide

[0105] Step 1: Conversion of Ester 7a (formula VII, n=1, R¹=H, R²=R³=Me)to Amide 8 (formula VIII n=1, R¹=H, R²=Me):

[0106] Ester 7a (93.6% ee; 0.93 g; 5.0 mmol) was combined with ammoniumhydroxide (28% NH₃; 1.0 mL; 15 mmol; 3 equiv) and stirred at ambienttemperature overnight, at which time tlc analysis indicated no 7a. Themixture was diluted with water (5 mL) and extracted with three 5 mLportions of dichloromethane. The combined extracts were dried withsodium sulfate and concentrated to afford 0.62 g (73%) of 8 whichpossessed 92.6% ee according to chiral GC analysis, indicating verylittle loss of enantiomeric purity. The crude product was recrystallizedfrom hot acetone (3.1 mL; 5 mL/g) by cooling to 0° C. The resultingcrystals were collected by filtration, washed with 1:1 acetone:heptane,and air-dried to afford 0.37 g (43%) of 8 which was 99.6% ee accordingto chiral GC.

[0107]¹H NMR (CDCl₃δ6.43 (br s, 1H); 5.72 (br s, 1 H); 4.455 (dd, 1H,J=9.07, 6.87 Hz); 3.38 (m, 2H); 2.40 (m, 2H); 2.1-1.9 (m, 3H); 1.67 (m,1H); 0.886 (t, 3H, J=7.42 Hz). Chiral GC analysis [Cyclosil-B (J&WScientific), 175° C. for 25 minutes, 15 psi He]: t_(R)=21.31 (Senantiomer), t_(R)=22.06 (R enantiomer)]. [α]_(D) ²²-86.7° (c 0.98,acetone).

[0108] Comparative Example: Conversion of Ester 7a (formula VII, n=1,R=H, R²=R³=Me) to Amide 8 (formula VIII, n=1, R¹=H, R²=Me):

[0109] Ester 7a (93.6% ee; 0.93 g; 5.0 mmol) was dissolved in 2 mL ofmethanol and treated with ammonium hydroxide (28% ammonia; 1.0 mL; 15mmol; 3 equiv). The mixture was stirred at ambient temperatureovernight, at which time tlc analysis indicated some residual 7a.Additional ammonium hydroxide (1.0 mL; 15 mmol; 3 equiv) was added andthe reaction mixture was stirred for 2 days to completely consume 7a.The reaction mixture was evaporated under reduced pressure andazeotroped several times with toluene under reduced pressure to afford0.95 g of 8 as a brown oil which was 89.4% ee according to chiral GCanalysis, indicating substantial loss of enantiomeric purity.

[0110] The invention has been described in detail with particularreference to specific aspects thereof, but it will be understood thatvariations and modifications can be effected without departing from thescope and spirit of the invention.

What is claimed is:
 1. A compound having the formula VII

wherein R¹, R², and R³ are, independently, hydrogen, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or substituted or unsubstituted C₄to C₂₀ heteroaryl group having at least one heteroatom, n is from 0 to5, and the stereochemistry at carbon a is substantially R or S.
 2. Thecompound of claim 1, wherein the stereochemistry at carbon a issubstantially S.
 3. The compound of claim 1, wherein the heteroatom ofthe heteroaryl group is oxygen, sulfur, or nitrogen, and the substituenton the substituted alkyl, aryl, or heteroaryl group comprises alkyl,aryl, hydroxy, alkoxy, fluoro, chloro, bromo, iodo, nitro, cyano, or anester.
 4. The compound of claim 1, wherein R² and R³ are independentlyselected from methyl or ethyl.
 5. The compound of claim 2, wherein R¹ ishydrogen, R² is methyl, R³ is methyl or ethyl, and n is
 2. 6. A methodfor producing the compound of claim 1, comprising hydrogenating anenamide having the formula VI

wherein R¹, R², R³, and n are as set forth in claim 1, with hydrogen inthe presence of a catalyst comprised of a chiral ligand/metal complex toasymmetrically hydrogenate the carbon-carbon double bond of the enamide.7. The method of claim 6, wherein the chiral ligand of the chiralligand/metal complex comprises a phosphine or a bis-phosphine compoundand the metal of the chiral ligand/metal complex comprises rhodium,ruthenium, or iridium.
 8. The method of claim 6, wherein the chiralligand of the chiral ligand/metal complex comprises a phosphine or abis-phosphine compound and the metal of the chiral ligand/metal complexcomprises rhodium.
 9. The method of claim 6, wherein the chiral ligandof the chiral ligand/metal complex comprises a substantiallyenantiomerically pure bis-phosphine compound comprising a substantiallyenantiomerically pure chiral backbone linking two phosphine residues,wherein one of the phosphine residues has three phosphorus-carbon bondsand the other phosphine residue has two phosphorus-carbon bonds and onephosphorus-nitrogen bond wherein the nitrogen is part of the chiralbackbone.
 10. The method of claim 6, wherein the chiral ligand of thechiral ligand/metal complex comprises a compound having the formula IXor X

where R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are, independently, hydrogen,substituted or unsubstituted branched or straight chain C₁ to C₂₀ alkyl,substituted or unsubstituted C₃ to C₈ cycloalkyl, substituted orunsubstituted C₆ to C₂₀ aryl, and substituted or unsubstituted C₄ to C₂₀heteroaryl, where the heteroatoms are chosen from sulfur, nitrogen, oroxygen, provided R¹² is not hydrogen; a is from0 and 3; b is from 0 and5; and M is a Group IV to Group VIII metal.
 11. The method of claim 10,wherein M comprises iron, ruthenium, or osmium.
 12. The method of claim10, wherein a and b are 0, R⁷ and R¹² are methyl, R⁸ and R⁹ are phenyl,and M is iron.
 13. The method of claim 6, wherein the chiral ligand ofthe chiral ligand/metal complex comprises the substantially pureenantiomer or diastereomer of2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane;2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;1,2-bis-2,5-dialkylphospholano(benzene);1,2-bis-2,5-dialkylphospholano(ethane);2,3-bis-(diphenylphosphino)butane; or2-diphenylphosphinomethyl-4-diphenylphophino-1-t-butoxycarbonylpyrrolidine.14. The method of claim 6, wherein the metal of the chiral ligand/metalcomplex is from 0.0005 to 0.5 equivalents per 1.0 equivalent of thecompound having the formula VI.
 15. The method of claim 6, wherein thehydrogenation step is conducted under an atmosphere of hydrogen at from0.5 to 200 atmospheres.
 16. The method of claim 6, wherein thehydrogenation step is conducted in a solvent comprising an aliphatichydrocarbon, an aromatic hydrocarbon, a cyclic ether, an acyclic ether,a halogenated hydrocarbon, a dialkyl ketone, a polar aprotic solvent, ora combination thereof.
 17. The method of claim 6, wherein thehydrogenation step is conducted at from −20° C. to 100° C.
 18. Acompound having the formula XI

wherein R¹, R³, and R⁴ are, independently, hydrogen, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or substituted or unsubstituted C₄to C₂₀ heteroaryl group, and n is from 0 to
 5. 19. The compound of claim18, wherein n is
 2. 20. The compound of claim 18, wherein R¹, R³, and R⁴are hydrogen and n is
 2. 21. The compound of claim 18, wherein R¹ ishydrogen, R³ and R⁴ are methyl, and n is
 2. 22. A method for producing acompound having the formula II,

wherein R¹ is hydrogen, substituted or unsubstituted, branched orstraight chain C₁ to C₂₀ alkyl; substituted or unsubstituted C₃ to C₈cycloalkyl; substituted or unsubstituted C₆ to C₂₀ aryl; or substitutedor unsubstituted C₄ to C₂₀ heteroaryl, and n is from 0 to 5, comprisingreacting a compound having the formula I

with glyoxylic acid.
 23. The method of claim 22, wherein the glyoxylicacid is present in the amount from 0.8 to 2 equivalents per 1.0equivalent of the compound having the formula I.
 24. A method forproducing the compound having the formula III,

wherein R¹, R³, and R⁴ are, independently, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or a substituted or unsubstituted C₄to C₂₀ heteroaryl group, wherein R¹ can also be hydrogen, and n is from0 to 5, comprising reacting the compound having formula II

 with an alcohol comprising an alkyl alcohol, an aryl alcohol, or aheteroaryl alcohol, wherein the alkyl alcohol is substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl or substitutedor unsubstituted C₃ to C₈ cycloalkyl; the aryl alcohol is substituted orunsubstituted C₆ to C₂₀ aryl; and the heteroaryl alcohol is substitutedor unsubstituted C₄ to C₂₀ heteroaryl, wherein the heteroatom is oxygen,nitrogen, or sulfur.
 25. The method of claim 24, wherein the alcohol isa C₁ to C₅ alcohol.
 26. The method of claim 24, wherein the alcohol ismethanol or ethanol.
 27. The method of claim 24, wherein the alcohol ispresent in the amount from 2.0 to 5.0 equivalents per 1.0 equivalent ofthe compound having the formula II.
 28. The method of claim 24, furthercomprising a dehydrating agent.
 29. A compound having the formula V

wherein R¹ and R³ are, independently, substituted or unsubstituted,branched or straight chain C₁ to C₂₀ alkyl; substituted or unsubstitutedC₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ to C₂₀ aryl; orsubstituted or unsubstituted C₄ to C₂₀ heteroaryl, wherein R¹ can alsobe hydrogen, R⁶ is substituted or unsubstituted, branched or straightchain C₁ to C₂₀ alkyl or substituted or unsubstituted C₃ to C₈cycloalkyl, and n is from 0 to
 5. 30. The compound of claim 29, whereinn is 2 and R¹ is hydrogen.
 31. The compound of claim 30, wherein R³ ismethyl or ethyl.
 32. The compound of claim 31, wherein R⁶ is methyl orethyl.
 33. A method of producing the compound of claim 29, comprisingreacting a compound having the formula IV

wherein R¹ and R³ are, independently, substituted or unsubstituted,branched or straight chain C₁ to C₂₀ alkyl; substituted or unsubstitutedC₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ to C₂₀ aryl; orsubstituted or unsubstituted C₄ to C₂₀ heteroaryl, wherein R¹ can alsobe hydrogen, X is fluoride, chloride, bromide, or iodide, and n is from0 to 5, with a phosphite having the formula P(OR⁶)₃, wherein R⁶ issubstituted or unsubstituted, branched or straight chain C₁ to C₂₀ alkylor substituted or unsubstituted C₃ to C₈ cycloalkyl.
 34. The method ofclaim 33, wherein X is chloride or bromide.
 35. The method of claim 33,wherein R is methyl or ethyl.
 36. The method of claim 33, wherein thephosphite is present in the amount from 0.8 to 1.2 equivalents per 1.0equivalent of the compound having the formula IV.
 37. A method ofproducing a compound having the formula IV,

wherein R¹ and R³ are, independently, substituted or unsubstituted,branched or straight chain C₁ to C₂₀ alkyl; substituted or unsubstitutedC₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ to C₂₀ aryl; orsubstituted or unsubstituted C₄ to C₂₀ heteroaryl, wherein R¹ can alsobe hydrogen, X is fluoride, chloride, bromide, or iodide, and n is from0 to 5, comprising reacting a compound having the formula III

wherein R¹, R³, and R⁴ are, independently, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or a substituted or unsubstituted C₄to C₂₀ heteroaryl group, wherein R¹ can also be hydrogen, and n is from0 to 5, with a compound having the formula PX₃, wherein X is fluoro,chloro, bromo, or iodo.
 38. A compound having the formula VI

wherein R¹, R², and R³ are, independently, hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl, and n isfrom 0 to
 5. 39. The compound of claim 38, wherein n is 2 and R¹ ishydrogen.
 40. The compound of claim 39, wherein R² and R³ are methyl.41. The compound of claim 39, wherein R² is methyl and R³ is ethyl. 42.A method for producing the compound of claim 38, comprising reacting acompound having the formula V

wherein R¹ and R³ are, independently, substituted or unsubstituted,branched or straight chain C₁ to C₂₀ alkyl; substituted or unsubstitutedC₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ to C₂₀ aryl; orsubstituted or unsubstituted C₄ to C₂₀ heteroaryl, wherein R¹ can behydrogen, R⁶ is substituted or unsubstituted, branched or straight chainC₁ to C₂₀ alkyl or substituted or unsubstituted C₃ to C₈ cycloalkyl, andn is from 0 to 5, with an aldehyde having the formula HC(O)R², whereinR² is hydrogen, substituted or unsubstituted, branched or straight chainC₁ to C₂₀ alkyl; substituted or unsubstituted C₃ to C₈ cycloalkyl;substituted or unsubstituted C₆ to C₂₀ aryl; or substituted orunsubstituted C₄ to C₂₀ heteroaryl in the presence of a base.
 43. Themethod of claim 42, wherein the base comprises an amidine base or aguanidine base.
 44. The method of claim 42, wherein the base comprises1,5-diazabicyclo(4.3.0)non-5-ene; 1,8-diazabicyclo(5.4.0)undec-7-ene, ortetramethylguanidine.
 45. The method of claim 42, wherein the base ispresent in the amount from 1.0 to 2.0 equivalents per 1.0 equivalent ofthe compound having the formula V.
 46. The method of claim 42, whereinthe aldehyde is present in the amount from 0.8 to 1.5 equivalents per1.0 equivalent of the compound having the formula V.
 47. The method ofclaim 42, wherein the aldehyde is acetaldehyde.
 48. A method forproducing the compound of claim 38 in situ, comprising (a) reacting acompound having the formula III

wherein R³ and R⁴ are, independently, hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group;substituted or unsubstituted C₃ to C₈ cycloalkyl group; substituted orunsubstituted C₆ to C₂₀ aryl group; or substituted or unsubstituted C₄to C₂₀ heteroaryl group, wherein R¹ can also be hydrogen with PX₃,wherein X is fluoride, chloride, bromide, or iodide, to produce ahalogenated lactam; (b) reacting the halogenated lactam produced in step(a) with a phosphite having the formula P(OR⁶)₃, wherein R⁶ issubstituted or unsubstituted, branched or straight chain C₁ to C₂₀ alkylor substituted or unsubstituted C₃ to C₈ cycloalkyl, to produce aphosphonated lactam; and (c) reacting the phosphonated lactam producedin step (b) with an aldehyde having the formula HC(O)R², wherein R² ishydrogen, substituted or unsubstituted, branched or straight chain C₁ toC₂₀ alkyl; substituted or unsubstituted C₃ to C₈ cycloalkyl; substitutedor unsubstituted C₆ to C₂₀ aryl; or substituted or unsubstituted C₄ toC₂₀ heteroaryl, in the presence of a base, wherein steps (a), (b), and(c) are performed in situ.
 49. A method for producing a compound havingthe formula VIII

wherein R¹ and R² are, independently, hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl, n isfrom 0 to 5, and the stereochemistry at carbon a is substantially R orS, comprising reacting a compound having the formula VII

wherein R³ is substituted or unsubstituted, branched or straight chainC₁ to C₂₀ alkyl; substituted or unsubstituted C₃ to C₈ cycloalkyl;substituted or unsubstituted C₆ to C₂₀ aryl; or substituted orunsubstituted C₄ to C₂₀ heteroaryl, with NH₄OH.
 50. The method of claim49, wherein the NH₄OH is present in the amount from 1 to 10 equivalentsper 1.0 equivalent of the compound having the formula VII.